N6 -substituted-adenosine-5'-uronamides as adenosine receptor modulator

Abstract

A series of adenosine-5'-uronamide derivatives bearing N6-arylurea, alkarylurea, heteroarylurea, arylcarbonyl, alkarylcarbonyl or heteroarylcarbonyl groups which have affinity and, in some cases, selectivity for the adenosine A1 or A3 receptors are disclosed. These compounds can be used in a pharmaceutical composition to treat disorders caused by excessive activation of the A1 or A3 receptors, or can be used in a diagnostic application to determine the relative binding of other compounds to the A1 or A3 receptors.

What is claimed is: 
     
       1. A compound of the following formula: ##STR3## wherein: R is hydrogen, alkyl, substituted alkyl, or aryl; R 1  is heteroaryl-NR--, heteroaryl-, or aryl-,   R 2  is hydrogen, alkyl, substituted alkyl, or aryl-NH--C(X)--,   R 3  and R 4  are independently selected from the group consisting of hydroxy, hydrogen, halo, azido, alkyl, alkoxy, carboxy, cyano, nitro, aryl, and amino,   wherein the heteroaryl groups are selected from the group consisting of furyl, indolizinyl, benzothienyl, isoxazolyl, thiadiazolyl, and pyridinyl;   wherein the aryl groups may optionally be substituted with from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, acyloxy, acylamino, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO 2  -alkyl, --SO 2  -substituted alkyl, --SO 2  -aryl, --SO 2  -heteroaryl and trihalomethyl,   wherein the heteroaryl groups may optionally be substituted with from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, acyloxy, acylamino, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO 2  -alkyl, --SO 2  -substituted alkyl, --SO 2  -aryl, --SO 2  -heteroaryl, and trihalomethyl, and   X is O.   
     
     
       2. The compound of claim 1 wherein R is hydrogen. 
     
     
       3. The compound of claim 1 wherein R 1  is aryl-. 
     
     
       4. The compound of claim 1 wherein R 1  is heteroaryl-NR--. 
     
     
       5. The compound of claim 1 wherein R 1  is heteroaryl-. 
     
     
       6. A compound selected from the group consisting of: N 6  -(4-biphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(2,4-dichlorobenzyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-methoxyphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-chlorophenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(phenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-sulfonamido-phenylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-acetyl-phenylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -((R)-α-phenylethylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -((S)-α-phenylethylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(5-methyl-isoxazol-3-yl-carbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(1,3,4-thiadiazol-2-yl-carbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -bis-(4-nitrophenylcarbamoylamino)-adenosine-5'-N-ethyluronamide, and   N 6  -bis-(5-chloro-pyridin-2-yl-carbamoylamino)-adenosine-5'-N-ethyluronamide.   
     
     
       7. A method of treating hypertension, or cardiac hypoxia, or providing protection against cerebral ischemia, comprising administering to a patient in need of treatment or protection thereof an effective amount of a compound of claim 1 which is an agonist or partial agonist of the A 3  receptor. 
     
     
       8. The method of claim 7 wherein R is hydrogen. 
     
     
       9. The method of claim 7 wherein R 2  is hydrogen. 
     
     
       10. A method of treating hypertension or cardiac hypoxia, or providing protection against cerebral ischemia, comprising administering to a patient in need of treatment or protection thereof an effective amount of a compound which is an agonist or partial agonist of the A 3  receptor, wherein the compound is selected from the group consisting of: N 6  -(benzylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-sulfonamido-phenylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-acetyl-phenylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -((R)-α-phenylethylcarbamoylamino)-adenosine-5'-N-ethyluronamide,   N 6  -((S)-α-phenylethylcarbamoylamino)-adenosine-5'-N-ethyluronamide, and   N 6  -bis-(4-nitrophenylcarbamoylamino)-adenosine-5'-N-ethyluronamide.   
     
     
       11. A method for providing cardioprotection, neuroprotection, pain management, treatment of adenosine-sensitive cardiac arrythmias, treatment of convulsion, treatment of glaucoma; treatment of sleep apnea; treatment of paroxysmal supraventricular tachycardia, protection against hypoxia or protection against ischemia induced injuries comprising administering to a patient in need of treatment thereof an effective amount of a compound of the following formula: ##STR4## wherein: R is hydrogen, alkyl, substituted alkyl or aryl; R 1  is heteroaryl-NR--, heteroaryl-, or aryl-,   R 2  is hydrogen, alkyl, substituted alkyl or aryl-NH--C(X)--,   R 3  and R 4  are independently selected from the group consisting of hydroxy, hydrogen, halo, azido, alkyl, alkoxy, carboxy, cyano, nitro, aryl, and amino,   wherein the heteroaryl groups are selected from the group consisting of furyl, indolizinyl, benzothienyl, isoxazolyl, thiadiazolyl, and pyridinyl;   wherein the aryl groups may optionally be substituted with from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, acyloxy, acylamino, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO 2  -alkyl, --SO 2  -substituted alkyl, --SO 2  -aryl, --SO 2  -heteroaryl and trihalomethyl,   wherein the heteroaryl groups may optionally be substituted with from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, acyloxy, acylamino, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO 2  -alkyl, --SO 2  -substituted alkyl, --SO 2  -aryl, --SO 2  -heteroaryl, and trihalomethyl, and   X is O,   which is active as an agonist or partial agonist of the A 1  receptor.   
     
     
       12. The method of claim 11 wherein R 1  is aryl-. 
     
     
       13. The method of claim 11 wherein R 1  is heteroaryl-NR--. 
     
     
       14. The method of claim 11 wherein R 1  is heteroaryl-. 
     
     
       15. A method for providing cardioprotection, neuroprotection, pain management, treatment of adenosine-sensitive cardiac arrhythmias, treatment of convulsion, treatment of glaucoma; treatment of sleep apnea; treatment of peroxysmal supraventricular tachycardia, protection against hypoxia or protection against ischemia induced injuries comprising administering to a patient in need of treatment thereof an effective amount of a compound selected from the group consisting of: N 6  -(4-biphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(2,4-dichlorobenzyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-methoxyphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(4-chlorophenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(phenyl-carbonylamino)-adenosine-5'-N-ethyluronamide,   N 6  -(5-methyl-isoxazol-3-yl-carbomayolamino)-adenoise-5'-N-ethyluromadine,   N 6  -91,3,4-thiadiazol-2-yl-carbamoylamino)-adenoise-5'-N-ethyluromadine, and   N 6  -(5-chloro-pyridin-2-yl-carbamoulamino)-adenoise-5'-N-ethyluromadine.